rs753153965

Variant names:

• chr11-107505007-C-G
• rs753153965
• NM_138775.3:c.1646G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-107505007-C-G
• chr11-107505007-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138775.3(ALKBH8):​c.1646G>C​(p.Gly549Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G549D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ALKBH8 NM_138775.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0490
• Publications: 0 publications found

Genes affected

ALKBH8 (HGNC:25189): (alkB homolog 8, tRNA methyltransferase) Enables tRNA (uracil) methyltransferase activity; tRNA binding activity; and zinc ion binding activity. Involved in cellular response to DNA damage stimulus; tRNA methylation; and tRNA wobble uridine modification. Located in cytosol and nuclear body. Implicated in autosomal recessive non-syndromic intellectual disability. [provided by Alliance of Genome Resources, Apr 2022]

ALKBH8 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal recessive 71

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07087079).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138775.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALKBH8	NM_138775.3	MANE Select	c.1646G>C	p.Gly549Ala	missense	Exon 12 of 12	NP_620130.2	Q96BT7-1
	ALKBH8	NM_001301010.3		c.1646G>C	p.Gly549Ala	missense	Exon 12 of 12	NP_001287939.2	Q96BT7-1
	ALKBH8	NM_001378133.1		c.1496G>C	p.Gly499Ala	missense	Exon 11 of 11	NP_001365062.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALKBH8	ENST00000428149.7	TSL:1 MANE Select	c.1646G>C	p.Gly549Ala	missense	Exon 12 of 12	ENSP00000415885.2	Q96BT7-1
	ALKBH8	ENST00000260318.6	TSL:1	n.*451G>C		non_coding_transcript_exon	Exon 9 of 9	ENSP00000260318.2	Q96BT7-2
	ALKBH8	ENST00000260318.6	TSL:1	n.*451G>C		3_prime_UTR	Exon 9 of 9	ENSP00000260318.2	Q96BT7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000635 AC: 1 AN: 157364 AF XY: 0.0000120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399410 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690198

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.0000280 AC: 1 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078902

Other (OTH) AF: 0.00 AC: 0 AN: 58064

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.9
DANN	Benign	0.40
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.049
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.023
Sift	Benign	0.44	T
Sift4G	Benign	0.70	T
Polyphen		0.28	B
Vest4		0.14
MutPred		0.22		Gain of helix (P = 0.0199)
MVP		0.12
MPC		0.012
ClinPred		0.10	T
GERP RS		2.1
Varity_R		0.023
gMVP		0.26
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs753153965; hg19: chr11-107375733;